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Next Up in NSCLC: Antibody-Drug Conjugates


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Antibody-drug conjugates directed against HER2, HER3, and trophoblast cell-surface antigen 2 (TROP2) are showing encouraging antitumor activity in advanced non–small cell lung cancer (NSCLC), according to research presented during the virtual edition of the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer Singapore.

TROPION-PanTumor01 Trial

Dato-DXd is directed against TROP2, a transmembrane glycoprotein that is highly expressed in NSCLC and other solid tumors. “High TROP2 expression is associated with a poor prognosis, which makes it a promising therapeutic target,” said Alexander Spira, MD, PhD, of Virginia Cancer Specialists, U.S. Oncology Research.

Alexander Spira, MD, PhD

Alexander Spira, MD, PhD

Dr. Spira reported the preliminary results of a phase I trial of 180 heavily pretreated patients with advanced or metastatic NSCLC unselected for TROP2 expression.1 Patients received Dato-DXd at 0.27 mg/kg to 10 mg/kg every 3 weeks. He focused on the 175 patients in the dose-expansion cohort. The majority of patients had received at least three or more prior lines of therapy, including platinum-based chemotherapy (94%), immunotherapy (84%), and tyrosine kinase inhibitors (17%).

Confirmed objective responses were observed in 23% of patients (n = 9/40) dosed at 4 mg/kg, 21% (n = 8/39) receiving 6 mg/kg, and 25% (n = 20/80) receiving 8 mg/kg, per blinded independent central review. Additionally, two patients who received 4 mg/kg, two patients treated with 6 mg/kg, and one patient treated with 8 mg/kg had suspected complete or partial responses, but longer follow-up is needed to confirm these findings, Dr. Spira said.

The disease control rate for 4 mg/kg, 6 mg/kg, and 8 mg/kg were 73%, 67%, and 80%, respectively. Preliminary median progression-free survival was 4.3 months, 8.2 months, and 5.4 months, respectively.

“A high percentage of patients had disease control, with few patients coming off study due to progressive disease,” Dr. Spira reported. “At data cutoff, some patients were ongoing [with treatment] for more than a year.”

At the recommended dose of 6 mg/kg, the safety profile was manageable. Notably, grade ≥ 3 treatment-emergent adverse events were observed in 10% of patients given 4 mg/kg, 16% of those who received 6 mg/kg, and 34% of those given 8 mg/kg. These adverse events were considered serious in 8%, 9%, and 20% of patients, respectively. Treatment-related interstitial lung disease was observed in 14 of 175 patients (8%), although at doses of 4 mg/kg and 6 mg/kg, this was seen in only 2 patients.

Based on these findings, the 6-mg/kg dose of datopotamab deruxtecan will be evaluated vs docetaxel in the registrational, randomized phase III TROPION-Lung01 trial. Participants will include patients without actionable mutations previously treated with platinum-based chemotherapy and antibodies targeting PD-1 or its ligand (PD-L1), either in combination or sequentially. The primary endpoints will be progression-free survival and overall survival.

Phase I Trial of Patritumab Deruxtecan

The HER3-directed antibody-drug conjugate patritumab deruxtecan continued to demonstrate clinically meaningful antitumor activity and a manageable safety profile at the recommended expansion dose of 5.6 mg/kg in pretreated patients with metastatic or unresectable NSCLC harboring EGFR mutations. This result was based on a phase I study presented by Helena A. Yu, MD, of Memorial Sloan Kettering Cancer Center. New York.2

Helena A. Yu, MD

Helena A. Yu, MD

“Patients with advanced EGFR-mutant NSCLC have few treatment options after failure on EGFR-targeted tyrosine kinase inhibitors and standard platinum-based chemotherapy,” Dr. Yu noted. “The HER3 protein is expressed on most lung cancers, including about 80% of EGFR-mutant NSCLC, and is associated with worse clinical outcomes. Its near-universal expression suggests HER3 as a promising therapeutic target, and there are currently no approved HER3-directed treatments.”

Patritumab deruxtecan comprises a fully human anti-HER3 IgG1 monoclonal antibody covalently linked to a topoisomerase 1 inhibitor payload via a tetrapeptide-based cleavable linker. The phase I study reported at the meeting included heavily pretreated EGFR-mutant NSCLC (median, four prior regimens). The dose-escalation phase involved patients who had experienced disease progression on osimertinib or who were T790M-negative after disease progression on erlotinib, gefitinib, or afatinib. The dose-expansion cohort included patients who had received at least one prior EGFR-targeted tyrosine kinase inhibitor and at least one prior platinum-based regimen.

Patients received 5.6 mg/kg of HER3-DXd every 3 weeks and were followed for a median of 5 months. Of 56 evaluable patients, 14 (25%) had a confirmed objective response per blinded independent central review, 1 (2%) being a complete response; 25 (45%) achieved stable disease, for a disease control rate of 70%. The median time to response was 2.0 months, and the median duration of response was 6.9 months.

“HER3-DXd at 5.6 mg/kg demonstrated antitumor activity in EGFR-mutated NSLC with known tyrosine kinase resistance mechanisms and in those without a clear mechanism of resistance,” Dr. Yu reported. “Treatment led to decreases in tumor size within 3 months.”

Patritumab deruxtecan had a manageable safety profile. The most common grade ≥ 3 treatment-emergent adverse effects were thrombocytopenia (28%) and neutropenia (19%). Three patients (5.3%) developed interstitial lung disease thought to be related to treatment.

Exploratory biomarker analyses showed almost all evaluable tumors expressed membrane HER3 at baseline, with a median membrane H score of 180 out of 300. Moreover, various resistance mechanisms to EGFR-targeted tyrosine kinase inhibitors were identified in pretreatment biopsies and circulating tumor DNA, including alterations in almost 10 different mutations. Responses were observed in many of these patients.

“HER3-DXd had clinically meaningful antitumor activity in patients with diverse tyrosine kinase inhibitor resistance mechanisms. It was effective in patients with on-target resistance, including MET amplifications, HER2 mutations, BRAF fusions, and PIK3CA mutations,” reported Dr. Yu.

The phase II HERTHENA-Lung01 study, launching in 2021, will evaluate single-agent patritumab deruxtecan in patients after failure of tyrosine kinase inhibitors and platinum-based chemotherapy.

DESTINY-Lung01 Trial Results

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-HER2 antibody, a linker, and a topoisomerase 1 inhibitor payload; it is approved in the treatment of metastatic breast

Kazuhiko Nakagawa, MD

Kazuhiko Nakagawa, MD

cancer. It may also be beneficial in NSCLC, according to the results of the phase II -DESTINY-Lung01 trial, presented by Kazuhiko Nakagawa, MD, of Kindai University Hospital, Osaka, Japan, during another session of the World -Conference on Lung Cancer.3

Cohort 1 included 49 extensively treated patients with HER2-overexpressing (defined as immunohistochemistry 3+ [IHC3+] or IHC2+) metastatic NSCLC treated with T-DXd at 6.4 mg/kg.3 Interim results, analyzed after a median 6.1 months of follow-up, showed no apparent differences in response by HER2 expression (IHC3+ vs IHC2+).

Confirmed objective responses, by independent central review, were observed in 24.5% of patients, one of which (2.6%) was a complete response. The disease control rate was 69.4%, the median progression-free survival was 5.4 months, the median duration of response was 6.0 months, and the median overall survival was 11.3 months, Dr. Nakagawa reported.

KEY POINTS

  • Antibody-drug conjugates are showing promising activity in advanced NSCLC.
  • Phase I trials evaluated the HER2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) and the anti-TROP2 antibody-drug conjugate patritumab deruxtecan (HER3-DXd).
  • With Dato-DXd, confirmed response rates of between 21% and 25% were observed, with disease control rates of between 73% and 80% and a median progression-free survival surpassing 8 months.
  • With HER3-DXd, the confirmed response rate was 25%, and the disease control rate was 70%; the drug was active across a variety of EGFR mutations.

In the HER2-overexpressing cohort of DESTINY-Lung01, there were eight cases of treatment-related interstitial lung disease or pneumonitis; they were grade 1 in two patients, grade 2 in three patients, and grade 5 (deaths) in five patients.

“Drug-related interstitial lung disease occurred in 16.3% of patients, with fatal outcomes observed in 6.1%. Interstitial lung disease continues to be closely monitored and proactively managed, with further investigations as more follow-up data become available,” Dr. Nakagawa said. 

DISCLOSURE:Dr. Spira holds ownership interests in Bayer, Gritstone Oncology, and Jazz Pharmaceuticals; has served in an institutional consulting or advisory role for Array BioPharma, AstraZeneca/MedImmune, Bristol Myers Squibb, and Merck; has received research funding from LAM Therapeutics; and has received institutional research funding from AbbVie, ADCT, Amgen, Arch Therapeutics, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gritstone, Ignyta, Incyte, Janssen Oncology, Loxo, MacroGenics, MedImmune, Mirati Therapeutics, NewLink Genetics, Novartis, Plexxikon, Roche, Rubius, Takeda, and Trovagene. Dr. Yu has served as a consultant or advisor to AstraZeneca, Blueprint Medicines, Daiichi Sankyo, and Janssen; has received institutional research funding from Astellas Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo, Lilly, Novartis, and Pfizer; has been reimbursed for travel, accommodations, or other expenses by Lilly; and has held other relationships with Astellas Pharma. Dr. Nakagawa has received honoraria from AbbVie, Amgen, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, CareNet, Chugai Pharma, Kyowa Kirin, Kyorin Pharmaceutical, Lilly, Medical Mobile Communications, Medical Review, Merck Biopharma, MSD KK, Nikkei Business Publications, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Roche Diagnostics KK, Taiho Pharmaceutical, Takeda Pharmaceutical, Yodosha, and 3H Clinical Trial; has served as a consultant or advisor to Eli Lilly Japan KK, Kyorin Pharmaceutical, Ono Pharmaceutical, and Pfizer Japan; and has received institutional research funding from A2 Healthcare, AbbVie, AstraZeneca KK, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharma, Covance Japan, Daiichi Sankyo, Eisai, EPS, GlaxoSmithKline KK, IQVIA Services Japan KK, Japan Clinical Research Operations, Kissei Pharmaceutical, Lilly, Medical Research Support, Mochida Pharmaceutical, MSD KK, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Parexel International, Pfizer, PPD-SNBL KK, PRA Health Sciences, Sanofi KK, SymBio Pharmaceuticals, Syneos Health, Sysmex Corporation, Taiho Pharmaceutical, and Takeda.

REFERENCES

1. Spira A, Lisberg AE, Sands JM, et al: Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: Updated results of TROPION-PanTumor01 phase 1 study. 2020 World Conference on Lung Cancer. Abstract OA03.03. Presented January 29, 2021.

2. Helena YA, Baik C, Gold K, et al: Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. 2020 World Conference on Lung Cancer. Abstract OA03.04. Presented January 29, 2021.

3. Nakagawa K, Nagasaka M, Felip E, et al: Trastuzumab deruxtecan in HER2-overexpressing metastatic non-small cell lung cancer: Interim results of DESTINY-Lung01. 2020 World Conference on Lung Cancer. Abstract OA04.05. Presented January 29, 2021.


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